PROJECT SUMMARY Intestinal homeostasis is controlled by a strict balance between cell proliferation in the crypts and cell shedding from the villi. Dysregulation of intestinal homeostasis is known to cause severe intestinal pathologies, including inflammatory bowel diseases (IBD) and gastrointestinal cancer. Although much progress has been made towards understanding how this complex epithelial system maintains homeostasis, whether and how lipid metabolism may influence the epithelial cells along the crypt-villus axis during homeostatic and diseased states has been largely unexplored. Recent studies from our lab has identified critical functions of lysophosphatidylcholine acyltransferase 3 (Lpcat3), a phospholipid (PL) remodeling enzyme, in intestine. Loss of Lpcat3 in intestine selectively reduces polyunsaturated phosphatidylcholine (PC) in membranes, leading to decreased membrane fluidity and curvature, and impaired lipid absorption. Our following studies discovered that Lpcat3 and PL remodeling also play important roles in intestinal stem cell (ISC) proliferation and the maintenance of homeostasis. However, the mechanisms by which Lpcat3 affects intestinal homeostasis are not clear. The primary aim of this proposal is to understand how Lpcat3 and phospholipid remodeling regulate ISC proliferation and intestinal homeostasis. Aim 1 will examine if Lpcat3 deficiency affects proliferation and differentiation of ISCs, and test if different PC species regulate crypt proliferation using ex vivo crypt organoid culture. Aim 2 will unravel the mechanisms by which loss of Lpcat3 promotes crypt proliferation. Aim 3 will determine if PC remodeling and cholesterol metabolism may contribute to intestinal tumorigenesis. The candidate has a background in lipid metabolism and cancer biology. His long term scientific goal is to unravel the molecular mechanisms underlying lipid metabolism and human diseases. To further prepare himself for his long-term research goal, he plans to seek training that will complement his existing technical skills and further develop his professional skills. UCLA has a highly collaborative environment ideal to this project and for him to achieve these goals. His mentor, Dr. Peter Tontonoz, is a highly respected scientist with expertise in the areas of nuclear receptors, inflammation and lipid metabolism. The applicant also has an advisory committee that consists of Dr. Martin G Martn, an accomplished gastrointestinal biologist and expert in intestinal stem cell biology, Dr. Steve Bensinger, an internationally recognized expert in lipid metabolism/mass spectrometry, and Dr. Stephen Young, a pioneer and expert in lipid metabolism in intestine. His mentor team has a detailed plan to facilitate his research progress and scientific career development. In summary, his educational and research experience together with a strong and supportive mentoring team make him an ideal candidate for this research project and the K01 award.